Hypoparathyroidism in Children



This chapter focuses on the rare disorder of hypoparathyroidism in children. It details the clinical features, pathophysiology, and biochemical abnormalities of the many forms seen clinically. Up-to-date information about the genetics of these disorders is provided along with the abnormalities in gene function. The chapter concludes with a summary of current treatment options for children with these disorders.


Hypoparathyroidism Ionized calcium Hypocalcemia Parathyroid hormone Distal renal tubular reabsorption Urinary calcium Renal 1 alpha hydroxylase 1,25 Dihydroxy vitamin D Seizures Laryngospasm Cardioversion disturbances Neuromuscular irritability Currently Paresthesias Chvostek sign Trousseau sign Mental retardation Dental hypoplasia Psychological manifestations Radiological signs Metaphysis Basal ganglia Calcifications of basal ganglia FARR syndrome Phosphatemia Hypomagnesemia Embryological development Transcription factors Calcium sensing receptors DiGeorge syndrome Fluorescent in situ hybridization TBX.1 gene Microcephaly Hypertelorism Cleft palate Micrognathia Philtrum Thymic aplasia Immunological disorders Urogenital, skeletal, ocular malformations Behavioral problems Glial cell missing B transcription factor Hypoparathyroidism Deafness Renal dysplasia syndrome Hypoparathyroidism Retardation Dysmorphism Kenny-Caffey syndrome Sanjad–Sakati syndrome Familial hypoparathyroidism X linked length recessive transmission SOX3 Deficiency of PTH production Heart is normal dominant hypocalcemia G protein coupled receptors Activating and inhibiting mutations Pseudo-Bartter syndrome Mutation in PTH gene Mitochondrial disease Kearns–Sayre syndrome Acquired hypoparathyroidism Calcium receptor antibodies APECED syndrome NA LP 5 protein Surgery Maternal hyperparathyroidism and neonatal hypoparathyroidism Iatrogenic causes of hypocalcemia Antiepileptic drugs Ketoconazole Aluminum hydroxide Laxatives Acute pancreatitis Rhabdomyolysis Treatment Increased urinary calcium excretion Nephrocalcinosis Calcium chelators Septic shock Infectious syndromes Chemotherapy Invasive tumors Alfacalcidol Lithiasis Exogenous PTH Teriparatide Osteosarcoma Autosomal dominant hypoparathyroidism Cytochrome P450 



The authors thank Richard Medeiros, Rouen University Hospital Medical Editor, for editing the manuscript.


  1. 1.
    Abugassa S, Nordenström J, Eriksson S, Sjödén G. Bone mineral density in patients with chronic hypoparathyroidism. J Clin Endocrinol Metab. 1993;76:1617–21.PubMedCrossRefGoogle Scholar
  2. 2.
    Fukunaga M, Otsuka N, Ono S, Kajihara Y, Nishishita S, Nakano Y, Yamamoto I, Torizuka K, Morita R. Computed tomography of basal ganglia calcifications in pseudo- and idiopathic hypoparathyroidism. Radiat Med. 1987;5:187–90.PubMedGoogle Scholar
  3. 3.
    Gordon J, Bennett AR, Blackburn CC, Manley NR. Gcm2 and Foxn1 mark early parathyroid- and thymus-specific domains in the developing third pharyngeal pouch. Mech Dev. 2001;103:141–3.PubMedCrossRefGoogle Scholar
  4. 4.
    Iascone MR, Vittorini S, Sacchelli M, Spadoni I, Simi P, Giusti S. Molecular characterization of 22q11 deletion in a three-generation family with maternal transmission. Am J Med Genet. 2002;108:319–21.PubMedCrossRefGoogle Scholar
  5. 5.
    Merscher S, Funke B, Epstein JA, Heyer J, Puech A, Lu MM, Xavier RJ, Demay MB, Russell RG, Factor S, Tokooya K, Jore BS, Lopez M, Pandita RK, Lia M, Carrion D, Xu H, Schorle H, Kobler JB, Scambler P, Wynshaw-Boris A, Skoultchi AI, Morrow BE, Kucherlapati R. TBX1 is responsible for cardiovascular defects in velo-cardio-facial/DiGeorge syndrome. Cell. 2001;104:619–29.PubMedCrossRefGoogle Scholar
  6. 6.
    Yagi H, Furutani Y, Hamada H, Sasaki T, Asakawa S, Minoshima S, Ichida F, Joo K, Kimura M, Imamura S, Kamatani N, Momma K, Takao A, Nakazawa M, Shimizu N, Matsuoka R. Role of TBX1 in human del22q11.2 syndrome. Lancet Engl. 2003;362(9393):1366–73.CrossRefGoogle Scholar
  7. 7.
    Van Esch H, Groenen P, Nesbit M, Schuffenhauer S, Lichtner P, Vanderlinden G, Harding B, Beetz R, Bilous R, Holdaway I, Shaw N, Fryns J, Van de Ven W, Thakker R, Devriendt K. GATA3 haplo-insufficiency causes human HDR syndrome. Nature. 2000;406:419–22.PubMedCrossRefGoogle Scholar
  8. 8.
    Kobrynski LJ, Sullivan KE. Velocardiofacial syndrome, DiGeorge syndrome: the chromosome 22q11.2 deletion syndromes. Lancet. 2007;370:1443–52.PubMedCrossRefGoogle Scholar
  9. 9.
    Paylor R, Glaser B, Mupo A, Ataliotis P, Spencer C, Sobotka A, Sparks C, Choi CH, Oghalai J, Curran S, Murphy KC, Monks S, Williams N, O’Donovan MC, Owen MJ, Scambler PJ, Lindsay E. Tbx1 haploinsufficiency is linked to behavioral disorders in mice and humans: implications for 22q11 deletion syndrome. Proc Natl Acad Sci USA. 2006;103:7729–34.PubMedCrossRefGoogle Scholar
  10. 10.
    Momma K. Cardiovascular anomalies associated with chromosome 22q11.2 deletion syndrome. Am J Cardiol. 2010;105:1617–24.PubMedCrossRefGoogle Scholar
  11. 11.
    Prasad SE, Howley S, Murphy KC. Candidate genes and the behavioral phenotype in 22q11.2 deletion syndrome. Dev Disabil Res Rev. 2008;14:26–34.PubMedCrossRefGoogle Scholar
  12. 12.
    Ding C, Buckingham B, Levine MA. Familial isolated hypoparathyroidism caused by a mutation in the gene for the transcription factor GCMB. J Clin Invest. 2001;108:1215–20.PubMedGoogle Scholar
  13. 13.
    Mannstadt M, Bertrand G, Muresan M, Weryha G, Leheup B, Pulusani SR, Grandchamp B, Jüppner H, Silve C. Dominant-negative GCMB mutations cause an autosomal dominant form of hypoparathyroidism. J Clin Endocrinol Metab. 2008;93:3568–76.PubMedCrossRefGoogle Scholar
  14. 14.
    Thomée C, Schubert SW, Parma J, Lê PQ, Hashemolhosseini S, Wegner M, Abramowicz MJ. GCMB mutation in familial isolated hypoparathyroidism with residual secretion of parathyroid hormone. J Clin Endocrinol Metab. 2005;90:2487–92.PubMedCrossRefGoogle Scholar
  15. 15.
    Liu Z, Yu S, Manley NR. Gcm2 is required for the differentiation and survival of parathyroid precursor cells in the parathyroid/thymus primordia. Dev Biol. 2007;305:333–46.PubMedCrossRefGoogle Scholar
  16. 16.
    Kebebew E, Peng M, Wong MG, Ginzinger D, Duh QY, Clark OH. GCMB gene, a master regulator of parathyroid gland development, expression, and regulation in hyperparathyroidism. Surgery. 2004;136:1261–6.PubMedCrossRefGoogle Scholar
  17. 17.
    Ali A, Christie PT, Grigorieva IV, Harding B, Van Esch H, Ahmed SF, Bitner-Glindzicz M, Blind E, Bloch C, Christin P, Clayton P, Gecz J, Gilbert-Dussardier B, Guillen-Navarro E, Hackett A, Halac I, Hendy GN, Lalloo F, Mache CJ, Mughal Z, Ong AC, Rinat C, Shaw N, Smithson SF, Tolmie J, Weill J, Nesbit MA, Thakker RV. Functional characterization of GATA3 mutations causing the hypoparathyroidism-deafness-renal (HDR) dysplasia syndrome: insight into mechanisms of DNA binding by the GATA3 transcription factor. Hum Mol Genet. 2007;16:265–75.PubMedCrossRefGoogle Scholar
  18. 18.
    Benetti E, Murer L, Bordugo A, Andreetta B, Artifoni L. 10p12.1 Deletion: HDR phenotype without DGS2 features. Exp Mol Pathol. 2009;86:74–6.PubMedCrossRefGoogle Scholar
  19. 19.
    Nesbit MA, Bowl MR, Harding B, Ali A, Ayala A, Crowe C, Dobbie A, Hampson G, Holdaway I, Levine MA, McWilliams R, Rigden S, Sampson J, Williams AJ, Thakker RV. Characterization of GATA3 mutations in the hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome. J Biol Chem. 2004;279:22624–34.PubMedCrossRefGoogle Scholar
  20. 20.
    Bernardini L, Sinibaldi L, Capalbo A, Bottillo I, Mancuso B, Torres B, Novelli A, Digilio MC, Dallapiccola B. HDR (hypoparathyroidism, deafness, renal dysplasia) syndrome associated to GATA3 gene duplication. Clin Genet. 2009;76:117–9.PubMedCrossRefGoogle Scholar
  21. 21.
    Parvari R, Diaz GA, Hershkovitz E. Parathyroid development and the role of tubulin chaperone E. Horm Res. 2007;67:12–21.PubMedCrossRefGoogle Scholar
  22. 22.
    Courtens W, Wuyts W, Poot M, Szuhai K, Wauters J, Reyniers E, Eleveld M, Diaz G, Nöthen MM, Parvari R. Hypoparathyroidism-retardation-dysmorphism syndrome in a girl: a new variant not caused by a TBCE mutation – clinical report and review. Am J Med Genet A. 2006;140:611–7.PubMedGoogle Scholar
  23. 23.
    Hershkovitz E, Parvari R, Diaz GA, Gorodischer R. Hypoparathyroidism-retardation-dysmorphism (HRD) syndrome – a review. J Pediatr Endocrinol Metab. 2004;17:1583–90.PubMedCrossRefGoogle Scholar
  24. 24.
    Bowl MR, Nesbit MA, Harding B, Levy E, Jefferson A, Volpi E, Rizzoti K, Lovell-Badge R, Schlessinger D, Whyte MP, Thakker RV. An interstitial deletion–insertion involving chromosomes 2p25.3 and Xq27.1, near SOX3, causes X-linked recessive hypoparathyroidism. J Clin Invest. 2005;115:2822–31.PubMedCrossRefGoogle Scholar
  25. 25.
    Thakker RV. Diseases associated with the extracellular calcium-sensing receptor. Cell Calcium. 2004;35:275–82.PubMedCrossRefGoogle Scholar
  26. 26.
    Lienhardt A, Bai M, Lagarde JP, Rigaud M, Zhang Z, Jiang Y, Kottler ML, Brown EM, Garabédian M. Activating mutations of the calcium-sensing receptor: management of hypocalcemia. J Clin Endocrinol Metab. 2001;86:5313–23.PubMedCrossRefGoogle Scholar
  27. 27.
    Lienhardt A, Garabédian M, Bai M, Sinding C, Zhang Z, Lagarde JP, Boulesteix J, Rigaud M, Brown EM, Kottler ML. A large homozygous or heterozygous in-frame deletion within the calcium-sensing receptor’s carboxylterminal cytoplasmic tail that causes autosomal dominant hypocalcemia. J Clin Endocrinol Metab. 2000;85:1695–702.PubMedCrossRefGoogle Scholar
  28. 28.
    Gamba G, Friedman PA. Thick ascending limb: the Na(+):K (+):2Cl (−) co-transporter, NKCC2, and the calcium-sensing receptor, CaSR. Pflugers Arch. 2009;458:61–76.PubMedCrossRefGoogle Scholar
  29. 29.
    Watanabe S, Fukumoto S, Chang H, Takeuchi Y, Hasegawa Y, Okazaki R, Chikatsu N, Fujita T. Association between activating mutations of calcium-sensing receptor and Bartter’s syndrome. Lancet. 2002;360:692–4.PubMedCrossRefGoogle Scholar
  30. 30.
    Ahn TG, Antonarakis SE, Kronenberg HM, Igarashi T, Levine MA. Familial isolated hypoparathyroidism: a molecular genetic analysis of 8 families with 23 affected persons. Medicine (Baltimore). 1986;65:73–81.Google Scholar
  31. 31.
    Arnold A, Horst SA, Gardella TJ, Baba H, Levine MA, Kronenberg HM. Mutation of the signal peptide-encoding region of the preproparathyroid hormone gene in familial isolated hypoparathyroidism. J Clin Invest. 1990;86:1084–7.PubMedCrossRefGoogle Scholar
  32. 32.
    D’Amour P, Palardy J, Bahsali G, Mallette LE, DeLean A, Lepage R. The modulation of circulating parathyroid hormone immunoheterogeneity in man by ionized calcium concentration. J Clin Endocrinol Metab. 1992;74:525–32.PubMedCrossRefGoogle Scholar
  33. 33.
    Katsanos KH, Elisaf M, Bairaktari E, Tsianos EV. Severe hypomagnesemia and hypoparathyroidism in Kearns-Sayre syndrome. Am J Nephrol. 2001;21:150–3.PubMedCrossRefGoogle Scholar
  34. 34.
    Wilichowski E, Grüters A, Kruse K, Rating D, Beetz R, Korenke GC, Ernst BP, Christen HJ, Hanefeld F. Hypoparathyroidism and deafness associated with pleioplasmic large scale rearrangements of the mitochondrial DNA: a clinical and molecular genetic study of four children with Kearns-Sayre syndrome. Pediatr Res. 1997;41:193–200.PubMedCrossRefGoogle Scholar
  35. 35.
    Brown EM. Anti-parathyroid and anti-calcium sensing receptor antibodies in autoimmune hypoparathyroidism. Endocrinol Metab Clin N Am. 2009;38:437–45. x.CrossRefGoogle Scholar
  36. 36.
    Mayer A, Ploix C, Orgiazzi J, Desbos A, Moreira A, Vidal H, Monier JC, Bienvenu J, Fabien N. Calcium-sensing receptor autoantibodies are relevant markers of acquired hypoparathyroidism. J Clin Endocrinol Metab. 2004;89:4484–8.PubMedCrossRefGoogle Scholar
  37. 37.
    Gardner JM, Fletcher AL, Anderson MS, Turley SJ. AIRE in the thymus and beyond. Curr Opin Immunol. 2009;21:582–9.PubMedCrossRefGoogle Scholar
  38. 38.
    Wolff AS, Erichsen MM, Meager A, Magitta NF, Myhre AG, Bollerslev J, Fougner KJ, Lima K, Knappskog PM, Husebye ES. Autoimmune polyendocrine syndrome type 1 in Norway: phenotypic variation, autoantibodies, and novel mutations in the autoimmune regulator gene. J Clin Endocrinol Metab. 2007;92:595–603.PubMedCrossRefGoogle Scholar
  39. 39.
    Alimohammadi M, Björklund P, Hallgren A, Pöntynen N, Szinnai G, Shikama N, Keller MP, Ekwall O, Kinkel SA, Husebye ES, Gustafsson J, Rorsman F, Peltonen L, Betterle C, Perheentupa J, Akerström G, Westin G, Scott HS, Holländer GA, Kämpe O. Autoimmune polyendocrine syndrome type 1 and NALP5, a parathyroid autoantigen. N Engl J Med. 2008;358:1018–28.PubMedCrossRefGoogle Scholar
  40. 40.
    Alimohammadi M, Dubois N, Sköldberg F, Hallgren A, Tardivel I, Hedstrand H, Haavik J, Husebye ES, Gustafsson J, Rorsman F, Meloni A, Janson C, Vialettes B, Kajosaari M, Egner W, Sargur R, Pontén F, Amoura Z, Grimfeld A, De Luca F, Betterle C, Perheentupa J, Kämpe O, Carel JC. Pulmonary autoimmunity as a feature of autoimmune polyendocrine syndrome type 1 and identification of KCNRG as a bronchial autoantigen. Proc Natl Acad Sci USA. 2009;106:4396–401.PubMedCrossRefGoogle Scholar
  41. 41.
    Page C, Strunski V. Parathyroid risk in total thyroidectomy for bilateral, benign, multinodular goitre: report of 351 surgical cases. J Laryngol Otol. 2007;121:237–41.PubMedGoogle Scholar
  42. 42.
    Lienhardt-Roussie A, Linglart A, Garabedian M. Treatment of chronic hypocalcaemia during childhood. Arch Pediatr. 2008;15:650–2.PubMedCrossRefGoogle Scholar
  43. 43.
    Misselwitz J, Hesse V, Markestad T. Nephrocalcinosis, hypercalciuria and elevated serum levels of 1,25-dihydroxyvitamin D in children. Possible link to vitamin D toxicity. Acta Paediatr Scand. 1990;79:637–43.PubMedCrossRefGoogle Scholar
  44. 44.
    Weber G, Cazzuffi MA, Frisone F, de Angelis M, Pasolini D, Tomaselli V, Chiumello G. Nephrocalcinosis in children and adolescents: sonographic evaluation during long-term treatment with 1,25-dihydroxycholecalciferol. Child Nephrol Urol. 1988;9:273–6.PubMedGoogle Scholar
  45. 45.
    Winer KK, Sinaii N, Peterson D, Sainz B, Cutler GB. Effects of once versus twice-daily parathyroid hormone 1–34 therapy in children with hypoparathyroidism. J Clin Endocrinol Metab. 2008;93:3389–95.PubMedCrossRefGoogle Scholar
  46. 46.
    Linglart A, Rothenbuhler A, Gueorgieva I, Lucchini P, Silve C, Bougnères P. Long-term results of continuous subcutaneous recombinant PTH (1–34) infusion in children with refractory hypoparathyroidism. J Clin Endocrinol Metab. 2011;96(11):3308–12.PubMedCrossRefGoogle Scholar
  47. 47.
    Subbiah V, Madsen VS, Raymond AK, Benjamin RS, Ludwig JA. Of mice and men: divergent risks of teriparatide-induced osteosarcoma. Osteoporos Int. 2010;21:1041–5.PubMedCrossRefGoogle Scholar
  48. 48.
    Theman TA, Collins MT, Dempster DW, Zhou H, Reynolds JC, Brahim JS, Roschger P, Klaushofer K, Winer KK. PTH(1–34) replacement therapy in a child with hypoparathyroidism caused by a sporadic calcium receptor mutation. J Bone Miner Res. 2009;24:964–73.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Department of PediatricNational Reference Center for Calcium/Phosphorus metabolic diseasesLimogesFrance
  2. 2.Department of Pediatric EndocrinologyBicêtre-Paris-Sud hospital, French Center of Reference for rare disorders of calcium and phosphate metabolism and INSERM unit U986le Kremlin-BicêtreFrance

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